We introduce the second generation theranostic devices that integrate multiple targeting moieties (e.g., antibody- or aptamer-based) with two additional molecular components: (1) molecular computing in order to analyze obtained disease signatures;and (2) specific drug delivery triggered by the outcome of this computing. These devices will be capable of specific targeting of cells based on multiple disease markers, resulting in elimination of narrow subpopulations of cells, and improved treatment of malignancies. Over the next two years we will accomplished goals described in two aims: Aim 1. Demonstration and optimization of molecular computing cascades on the surface of the lymphocytes targeted with antibody- or aptamer-oligonucleotide conjugates. Molecular computing on cell surfaces will be based on cascades of chemical reactions that occur only if all required components of these cascades are present on the cell surface (cascaded AND gates) or protective factors are absent (cascaded NOT gates). Aim 2. Demonstration of drug delivery to the cells on the surface of which molecular cascades have been completed. Cells targeted for elimination with molecular computing will at the end of cascades display specific oligonucleotides, while non-target cells will not. We will construct various toxic agents integrated with an oligonucleotide complementary to the displayed one, and we will study their effects on cells treated with molecular computing cascades. The large multidisciplinary team ensures that at the end of the second year, we will have demonstrated all the components of cascades, putting us in a position to start optimization process needed for the first animal studies. PUBLIC HEALTH RELEVANCE: We propose that complex diseases and traits, such as many cancers, autoimmune diseases, or obesity, can be addressed through interactions with matching multi-input molecular networks or molecular automata. The successful completion of our project will lead to the following vision of personalized therapy: A physician determines the unique surface immunophenotype of a cell type that he/she would like to target for elimination from a patient. Guided by the comparison with the phenotypes of healthy cells, the physician combines off-the- shelf reagents, creating and administering automata to the patient, specifically killing the targeted cell types, while protecting non-target cells.